Cardiovascular Toxicology

, Volume 10, Issue 3, pp 190–198

T Lymphocyte Regulation of Lysyl Oxidase in Diet-Induced Cardiac Fibrosis

  • Sherma Zibadi
  • Randy Vazquez
  • Douglas F. Larson
  • Ronald R. Watson


Left ventricular diastolic dysfunction is an important predictor of prognosis and mortality of heart failure. Increased left ventricular stiffness can be associated with excessive myocardial fibrosis and increased cross-linked collagen by the enzyme lysyl oxidase (LOX). These cardiac extracellular matrix (ECM) remodeling processes are affected by T-lymphocyte function and phenotype. We sought to examine the role of T lymphocytes in myocardial LOX regulation in diet-induced fibrotic hearts. Female SCID mice, devoid of functional T lymphocytes, and wild-type (WT) C57BL/6 were treated with a high-fat high-simple carbohydrate (HFHSC) diet for 12 months. HFHSC-fed WT mice demonstrated a significant increase in the catalytic activity of myocardial LOX compared with respective controls. These changes coincided with a marked increase in ECM collagen cross-linking and impaired diastolic filling pattern. However, induction of LOX was minimal in the SCID mice compared with the WT group. Correspondingly fibrillar cross-linked collagen concentrations and diastolic dysfunction were less prominent in the SCID mice compared with the WT group. Our results suggest a role for T lymphocytes in this dietary induction of diastolic dysfunction through modulation of LOX-dependent collagen maturation.


Diastolic dysfunction Lymphocytes Lysyl oxidase Cross-linked collagen 


  1. 1.
    Owan, T. E., Hodge, D. O., Herges, R. M., Jacobsen, S. J., Roger, V. L., & Redfield, M. M. (2006). Trends in prevalence and outcome of heart failure with preserved ejection fraction. The New England Journal of Medicine, 355, 251–259.CrossRefPubMedGoogle Scholar
  2. 2.
    Kass, D. A., Bronzwaer, J. G. F., & Paulus, W. J. (2004). What mechanisms underlie diastolic dysfunction in heart failure? Circulation Research, 94, 1533–1542.CrossRefPubMedGoogle Scholar
  3. 3.
    Zile, M. R., Baicu, C. F., & Gaasch, W. H. (2004). Diastolic heart failure—Abnormalities in active relaxation and passive stiffness of the left ventricle. The New England Journal of Medicine, 350, 1953–1959.CrossRefPubMedGoogle Scholar
  4. 4.
    Badenhorst, D., Maseko, M., Tsotetsi, O. J., Naidoo, A., Brooksbank, R., Norton, G. R., et al. (2003). Cross-linking influences the impact of quantitative changes in myocardial collagen on cardiac stiffness and remodelling in hypertension in rats. Cardiovascular Research, 57, 632–641.CrossRefPubMedGoogle Scholar
  5. 5.
    Smith-Mungo, L. I., & Kagan, H. M. (1998). Lysyl oxidase: Properties, regulation and multiple functions in biology. Matrix Biology, 16, 387–398.CrossRefPubMedGoogle Scholar
  6. 6.
    Yndestad, A., Ueland, T., Oie, E., Florholmen, G., Halvorsen, B., Attramadal, H., et al. (2004). Elevated levels of activin a in heart failure—Potential role in myocardial remodeling. Circulation, 109, 1379–1385.CrossRefPubMedGoogle Scholar
  7. 7.
    Yu, Q. L., Watson, R. R., Marchalonis, J. J., & Larson, D. F. (2005). A role for T lymphocytes in mediating cardiac diastolic function. American journal of physiology Heart and circulatory physiology, 289, H643–H651.CrossRefPubMedGoogle Scholar
  8. 8.
    Yu, Q. L., Horak, K., & Larson, D. F. (2006). Role of T lymphocytes in hypertension-induced cardiac extracellular matrix remodeling. Hypertension, 48, 98–104.CrossRefPubMedGoogle Scholar
  9. 9.
    Zibadi, S., Yu, Q., Rohdewald, P. J., Larson, D. F., & Watson, R. R. (2007). Impact of Pycnogenol (R) on cardiac extracellular matrix remodeling induced by L-NAME administration to old mice. Cardiovascular Toxicology, 7, 10–18.CrossRefPubMedGoogle Scholar
  10. 10.
    Yang, B., Larson, D. F., Beischel, J., Kelley, R., Shi, J., & Watson, R. R. (2001). Validation of conductance catheter system for quantification of murine pressure-volume loops. International journal of surgical investigation, 14, 341–355.Google Scholar
  11. 11.
    Palamakumbura, A. H., & Trackman, P. C. (2002). A fluorometric assay for detection of lysyl oxidase enzyme activity in biological samples. Analytical Biochemistry, 300, 245–251.CrossRefPubMedGoogle Scholar
  12. 12.
    Zibadi, S., Vazquez, R., Moore, D., Larson, D. F., & Watson, R. R. (2009). Myocardial lysyl oxidase regulation of cardiac remodeling in a murine model of diet-induced metabolic syndrome. American journal of physiology Heart and circulatory physiology, 297, H976–H982.CrossRefPubMedGoogle Scholar
  13. 13.
    Smith-Mungo, L. I., & Kagan, H. M. (1998). Lysyl oxidase: Properties, regulation and multiple functions in biology. Matrix Biology, 16, 387–398.CrossRefPubMedGoogle Scholar
  14. 14.
    Lopez, B., Querejeta, R., Gonzalez, A., Beaumont, J., Larman, M., & Diez, J. (2009). Impact of treatment on myocardial lysyl oxidase expression and collagen cross-linking in patients with heart failure. Hypertension, 53, U236–U253.CrossRefGoogle Scholar
  15. 15.
    Kellar, R. S., Shepherd, B. R., Larson, D. F., Naughton, G. K., & Williams, S. K. (2005). Cardiac patch constructed from human fibroblasts attenuates reduction in cardiac function after acute infarct. Tissue engineering, 11, 1678–1687.CrossRefPubMedGoogle Scholar
  16. 16.
    Song, Y. L., Ford, J. W., Gordon, D., & Shanley, C. J. (2000). Regulation of lysyl oxidase by interferon-gamma in rat aortic smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 20, 982–988.PubMedGoogle Scholar
  17. 17.
    Tan, R. S. P., Taniguchi, T., & Harada, H. (1996). Identification of the lysyl oxidase gene as a target of the antioncogene transcription factor, IRF-1, and its possible role in tumor suppression. Cancer Research, 56, 2417–2421.PubMedGoogle Scholar
  18. 18.
    Shanley, C. J., GharaeeKermani, M., Sarkar, R., Welling, T. H., Kriegel, A., Ford, J. W., et al. (1997). Transforming growth factor-beta(1) increases lysyl oxidase enzyme activity and mRNA in rat aortic smooth muscle cells. Journal Vascular Surgery, 25, 446–452.CrossRefGoogle Scholar
  19. 19.
    Rodriguez, C., Alcudia, J. F., Martinez-Gonzalez, J., Raposo, B., Navarro, M. A., & Badimon, L. (2008). Lysyl oxidase (LOX) down-regulation by TNF alpha: A new mechanism underlying TNF alpha-induced endothelial dysfunction. Atherosclerosis, 196, 558–564.CrossRefPubMedGoogle Scholar
  20. 20.
    Hofnagel, O., Luechtenborg, B., Stolle, K., Lorkowski, S., Eschert, H., Plenz, G., et al. (2004). Proinflammatory cytokines regulate LOX-1 expression in vascular smooth muscle cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 1789–1795.CrossRefPubMedGoogle Scholar
  21. 21.
    Yu, Q. L., & Larson, D. F. (2007). Toll-like receptor induced il-12 and il-18 mediates cardiac ECM remodeling mediated by lysyl oxidase. Journal of Cardiac Failure, 13, 98.CrossRefGoogle Scholar
  22. 22.
    Garrigue-Antar, L., Hartigan, N., & Kadler, K. E. (2002). Post-translational modification of bone morphogenetic protein-1 is required for secretion and stability of the protein. Journal Biological Chemistry, 277, 43327–43334.CrossRefGoogle Scholar
  23. 23.
    Bock, O., Hoftmann, J., Theophile, K., Hussein, K., Wiese, B., Schlue, J., et al. (2008). Bone morphogenetic proteins are overexpressed in the bone marrow of primary myelofibrosis and are apparently induced by fibrogenic cytokines. American Journal of Pathology, 172, 951–960.CrossRefPubMedGoogle Scholar
  24. 24.
    Li, Y. Y., McTiernan, C. F., & Feldman, A. M. (2000). Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling. Cardiovascular Research, 46, 214–224.CrossRefPubMedGoogle Scholar
  25. 25.
    Messerli, F. H. (2004). TIMPs, MMPs and cardiovascular disease. European Heart Journal, 25, 1475–1476.CrossRefPubMedGoogle Scholar
  26. 26.
    Brown, R. D., Jones, G. M., Laird, R. E., Hudson, P., & Long, C. S. (2007). Cytokines regulate matrix metalloproteinases and migration in cardiac fibroblasts. Biochemical and Biophysical Research Communications, 362, 200–205.CrossRefPubMedGoogle Scholar
  27. 27.
    Siwik, D. A., Chang, D. L. F., & Colucci, W. S. (2000). Interleukin-1 beta and tumor necrosis factor-alpha decrease collagen synthesis and increase matrix metalloproteinase activity in cardiac fibroblasts in vitro. Circulation Research, 86, 1259–1265.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Sherma Zibadi
    • 1
    • 2
  • Randy Vazquez
    • 1
    • 3
  • Douglas F. Larson
    • 1
  • Ronald R. Watson
    • 1
    • 2
  1. 1.Sarver Heart Center, College of MedicineThe University of ArizonaTucsonUSA
  2. 2.Division of Health Promotion Sciences, Mel and Enid Zuckerman Arizona College of Public HealthThe University of ArizonaTucsonUSA
  3. 3.Department of Nutritional SciencesThe University of ArizonaTucsonUSA

Personalised recommendations